The effect of plasma protein binding of bupivacaine on its transfer into brain and salivary gland was studied using bovine serum albumin, human alpha 1-acid glycoprotein (AAG) and human serum. The in vivo brain extraction and salivary gland extraction of [3H] bupivacaine relative to [14C]butanol were determined with an intracarotid injection technique used on rats. The brain extraction varied inversely with the bovine serum albumin (0-7.5%) and AAG (0-3.0 mg/ml) concentrations. The salivary extraction only slightly varied inversely with the AAG concentration, whereas no significant effects of bovine albumin binding on salivary gland uptake were observed. The in vivo percentage of exchangeable drug in brain or salivary gland capillaries was severalfold greater than the in vitro percentage of unbound drug. The percent values of free drug, brain exchangeable drug and salivary exchangeable drug were 12 +/- 1, 81 +/- 7 and 93 +/- 18% for umbilical cord serum, 8.6 +/- 1.1, 73 +/- 6 and 103 +/- 3% for normal human serum, 5.9 +/- 0.5, 60 +/- 4 and 89 +/- 3% for serum of rheumatoid arthritis patients and 5.0 +/- 0.2, 45 +/- 2 and 83 +/- 3% for serum of metastatic cancer patients. These data indicate that bupivacaine is not transported through the brain capillary wall, i.e., the blood-brain barrier, from the bovine albumin-bound pool, but bupivacaine is partially available for transfer from the circulating AAG-bound pool. However, both bovine albumin-bound and AAG-bound bupivacaine are readily available for transport through salivary gland capillaries.(ABSTRACT TRUNCATED AT 250 WORDS)